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Oncotarget. 2015 Apr 20;6(11):9612-26.

Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation.

Author information

1
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
2
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
3
FACS Core Facility, Aarhus University, Aarhus, Denmark.
4
Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
5
Department of Hematology, Odense University Hospital, Odense, Denmark.

Abstract

The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023). Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.

KEYWORDS:

DNA methylation; T cells; hypomethylating agents; myelodysplastic syndromes; programmed death-1

PMID:
25823822
PMCID:
PMC4496243
DOI:
10.18632/oncotarget.3324
[Indexed for MEDLINE]
Free PMC Article

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